Dry eye syndrome (DES), also referred to as dry eye disease, is a highly prevalent ocular surface disease. Approximately 40 million Americans are affected with some type of dry eye, a significant portion of which that are age 50 years and older have moderate-to-severe dry eye (Schaumberg, Sullivan et al., 2003, Prevalence of dry eye syndrome among US women, Am J Ophthalmol (136): 318-326; Schaumberg, Dana et al., 2009, Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies, Arch Ophthalmol (127): 763-768).
Broadly, dry eye disease can be any syndrome associated with tear film instability and dysfunction (such as increased tear evaporation and/or reduced aqueous secretion). Among the indications that are referred to by the general term “dry eye disease” are: Keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, corneal injury, ocular surface infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamin deficiencies), pharmacologic side effects, glandular and tissue destruction, autoimmune and other immunodeficient disorders, and inability to blink in comatose patients. Also included are dry eye symptoms caused by environmental exposure to airborne particulates, smoke, smog, and excessively dry air; as well as contact lens intolerance and eye stress caused by computer work or computer gaming.
There are other diseases that have a high degree of co-morbidity with dry eye disease: Allergic conjunctivitis (seasonal and chronic), blepharitis and Meibomian gland dysfunction. These conditions affect the quality and stability of the tear film, which results in dry eye signs and symptoms.
Laser assisted vision correction procedures such as photorefractive keratectomy (PRK), laser-assisted sub-epithelial keratectomy (LASEK) and laser-assisted in situ keratomileusis (LASIK) also negatively influence tear film functionality and frequently cause (temporary) dry eye disease.
Currently the management of DES encompasses both pharmacologic and non-pharmacologic treatments, including environmental management, avoidance of exacerbating factors, lid hygiene, tear supplementation (artificial tears), secretagogues (to increase the production of tears), punctual plugs, anti-inflammatory agents (cyclosporine, steroids), moisture chamber, and even salivary gland auto transplantation (Behrens, Doyle et al., 2006, Dysfunctional tear syndrome: a Delphi approach to treatment recommendations, Cornea (25): 900-907). Currently available options for treating DES are inadequate. Even tear supplementation is not an ideal treatment option as it requires the subject to repeat artificial tear installation very many times during the day.
Various polymers have been disclosed as possible aids in providing some benefit to alleviating DES symptoms and in fact some artificial tears contain one or more polymers, including the currently top 5 best selling over-the-counter (OTC) products for dry eye within the EU (Celluvisc®, Systane®, Hylo-Comod®, Optive® and Artelac®). These polymers are intended to protect ocular mucous membranes and provide lubrication for the ocular surface. Examples include cellulose derivatives, hyaluronic acid, liquid polyols, polyvinyl alcohol, povidone, carbopol and hydroxypropyl-guar. Polymers used in products to treat DES have relatively short residence time on the ocular surface and require frequent instillation. In order to increase ocular residence time, some formulations contain petroleum jelly or mineral oil; however, due to significant blurring these highly viscous products can only be used in the evening prior to sleep. (Abelson et al., 2008, Tear Substitutes. In: Albert and Miller, eds. Principles and Practices of Ophthalmology, 3rd edition, vol. 1. Philadelphia: W.B. Saunders Company, 287-292). All other tear substitutes have to be instilled repeatedly during the day.
Some potential improvements to these polymers have been disclosed. One potential improvement could be to use a polymer that has significant mucoadhesive properties in order to increase residence time of the formulation on the ocular surface without causing significant blurring. Chitosan, a polycationic polymer which is derived from the natural polymer chitin, is well known for its mucoadhesive properties. Ocular residence time of ophthalmic formulations containing chitosan can be increased not only due to its viscosity enhancing properties but also because of interactions of chitosan with negatively charged mucins on the ocular surface (Wadhwa, Paliwal et al., 2009, Chitosan and its role in ocular therapeutics, Mini Rev Med Chem (9): 1639-1647). In addition, chitosan has antimicrobial activity against various pathogenic microorganisms (Felt, Carrel et al., 2000, Chitosan as tear substitute: a wetting agent endowed with antimicrobial efficacy, J Ocul Pharmacol Ther (16): 261-270; Dai, Tanaka et al., 2011, Chitosan preparations for wounds and burns: antimicrobial and wound-healing effects, Expert Rev Anti Infect Ther (9): 857-879).
Thiolation of polymers has been disclosed to further increase their mucoadhesive properties. EP 1126881 B1 discloses a mucoadhesive polymer comprising at least one non-terminal thiol group. The use of thiolated polysaccharides for preparing an implant for tissue augmentation is disclosed in WO 2008/077172, wherein said thiolated polymers are characterised by the formation of disulfide bonds which leads to a stabilisation of the polymeric network. The priority application of WO 2008/077172, A 2136/2006, discloses further application fields for thiolated polymers.
Modification of chitosan by covalent attachment of thiol group bearing ligands (i.e., thiolation) has been disclosed. It has also been disclosed that thiolation increases the mucoadhesive properties of chitosan (Kast and Bernkop-Schnurch, 2001, Thiolated polymers—thiomers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates, Biomaterials (22): 2345-2352; Bernkop-Schnurch, Hornof et al., 2004, Thiolated chitosans, Eur J Pharm Biopharm (57): 9-17; Bernkop-Schnurch, 2005, Thiomers: a new generation of mucoadhesive polymers, Adv Drug Deliv Rev (57): 1569-1582; Schmitz, Grabovac et al., 2008, Synthesis and characterization of a chitosan-N-acetyl cysteine conjugate, Int J Pharm (347): 79-85). The antimicrobial efficacy of some thiolated chitosans was evaluated as well (WO2009132226 A1; WO2009132227 A1; WO2009132228 A1; Geisberger, Gyenge et al., 2013, Chitosan-thioglycolic acid as a versatile antimicrobial agent, Biomacromolecules (14): 1010-1017)
N-acetylcysteine (NAC) is a derivative of the thiol group bearing amino acid L-cysteine. NAC is a reducing agent with antioxidative activity. It is also well known for its ability to reduce mucus viscosity by reducing mucin disulfide bonds. Due to these mucolytic properties NAC is widely used to reduce mucus viscosity in broncho-pulmonary disorders with excessive mucus production. Topical ophthalmic formulations containing the mucolytic and antioxidant agent NAC are used for the treatment of corneal diseases such as meibomian gland dysfunction and DES (Lemp, 2008, Management of dry eye disease, Am J Manag Care (14): S88-101; Akyol-Salman, Azizi et al., 2010, Efficacy of topical N-acetylcysteine in the treatment of meibomian gland dysfunction, J Ocul Pharmacol Ther (26): 329-333). EP 0 551 848 B1 discloses an ophthalmic pharmaceutical composition for the treatment of DES containing NAC in a concentration between 3% and 5% (w/v) and polyvinylalcohol.
It has been disclosed that thiolation of chitosan using NAC increases its ocular residence time on rabbit eyes when compared with non-thiolated chitosan (Dangl, Hornof et al., 2009, In vivo Evaluation of Ocular Residence Time of 124I-labelled Thiolated Chitosan in Rabbits Using MicroPET Technology, ARVO Meeting Abstracts (50): 3689).
It has been disclosed that N—(N-acetylcysteinyl-)chitosan HCl has some beneficial effect on the ocular surface of the mouse eye in mouse dry eye models (Hongyok, Chae et al., 2009, Effect of chitosan-N-acetylcysteine conjugate in a mouse model of botulinum toxin B-induced dry eye, Arch Ophthalmol (127): 525-532; Hornof, Goyal et al., 2009, Thiolated Chitosan for the Treatment of Dry Eye—Evaluation in Mice Using the Controlled-Environment Chamber Model, ARVO Meeting Abstracts (50): 3663).
Further publications reviewing and discussing various uses of thiolated polymers are listed below:
Hornof et al., Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans; Journal of Controlled Release 89 (2003) 419-428; Hornof, M., In vitro and in vivo evaluation of novel polymeric excipients in the ophthalmic field, Thesis, University of Vienna, 2003; Bernkop-Schnurch et al., Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: Thiomer/GSH systems, J. Contr. Release 93 (2003) 95-103; M. Hornof et al., In Vitro Evaluation of the Permeation Enhancing Effect of Polycarbophil-Cystein Conjugates on the Cornea of Rabbits, J. Pharm. Sci. 91 (12) 2002, 2588-2592; and Clausen et al., The Role of Glutathione in the Permeation Enhancing Effect of Thiolated Polymers, Pharm. Res. 19 (5) 2002, 602-608; Yamashita et al., Synthesis and Evaluation of Thiol Polymers, J. Macromol. Sc. 26 (1989), 9, 1291-1304; Zheng et al., Disulfide Cross-Linked Hyaluronan Hydrogels, Biomacromolecules 3 (6) 2002, 1304-1311; Wang et al., Chitosan-NAC Nanoparticles as a Vehicle for Nasal Absorption Enhancement of Insulin, J. Biomed Mater Res Part B: Appl Biomater 88B: 150-161, 2009; WO 2008/094675 A2; U.S. Pat. No. 5,412,076 A.
However, so far no formulation containing thiolated chitosan has been disclosed which fulfills the requirements of long-term stability, tolerability, safety, effectiveness in the treatment of dry eye syndrome and improved patient compliance. As a result of the ineffectiveness and inconvenience of current therapies of dry eye treatment, there remains a need for a method of treating dry eye syndrome that fulfills the requirements listed above.